Several Ebola virus species have been associated with severe viral hemorrhagic fevers (VHF) in humans. Human infection typically occurs through contact with blood or bodily fluids from bats and other infected animals or humans. To date all of the significant Ebola virus outbreaks in central and western Africa have been from the Ebola- Zaire (EBOV), Sudan (SUDV) and Bundibugyo (BDBV) species with case-fatality rates ranging from 40-90%. The most significant recorded outbreak is currently underway this year and has a probable cumulative total of 1323 cases of Ebola hemorrhagic fever (EHF) and an estimated 729 fatalities to date highlighting the need for effective Ebola antivirals, for which there are currently none. Given the lack of effective treatments and prophylactics, the high mortality rate associated with infection, and the potential for geographical transplantation the development of broad spectrum Ebola virus antivirals for the treatment and prophylaxis of VHF is an NIAID priority. Here we propose to optimize two distinct chemical series that inhibit VSV pseudotype viruses expressing either the EBOV or BDBV glycoprotein but not that of the VSV glycoprotein. Some of the hit compounds from within both entry inhibitor chemical series exhibit submicromolar IC50s, low cytotoxicity and therapeutics indices of >10 or more. These chemical series represent attractive starting points for the development of novel Ebola virus antiviral therapeutics.